Drug-Herb Interactions: Mechanisms Involved and Clinical Implications of Five Commonly and Traditionally Used Herbs

Review Drug-herb interactions: Mechanisms involved and clinical implications of five commonly and traditionally used herbs Chin Eng Ong1,*, Yan Pan2 1School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 46150 Bandar Sunway, Selangor, Malaysia; 2School of Biomedical Sciences, The University of Nottingham Malaysia Campus, Jalan Broga, 43500 Semenyih, Selangor, Malaysia ABSTRACT Herbal remedies are commonly used by patients worldwide. Because these herbal preparations share the same metabolic and transport proteins with prescribed medicines, the potential for a drug-herb interaction is substantial and is an issue of significant concern. This review paper summarizes drug-herb interactions involving inhibition or induction of cytochrome P450 enzymes, drug transporters as well as modulation of drug pharmacodynamics. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and implications of these studies are discussed in this review. The most commonly implicated drugs in the interaction include anticoagulants, antiplatelets, immunosuppressants, anti-neoplastics, protease inhibitors, and some antidepressants. Pharmacokinetic and/or pharmacodynamic interactions of five commonly used herbal remedies (danshen, garlic, Ginkgo biloba, ginseng, and St John’s wort) with these drugs are presented, with focus of discussion being the potentials for interaction, their mechanisms and clinical implications. There is a necessity for adequate pharmacovigilance to be carried out in minimizing unanticipated but often preventable drug-herb interactions. Keywords cytochrome P450, drug-herb interaction, P-glycoprotein, pharmacodynamics, pharmacokinetics INTRODUCTION identity of the chemical constituents from a natural product is unknown. As a result, both adverse drug reactions and Patients usually take several drugs for the treatment of one or poisonings associated with the use of herbal remedies have more health problems at the same time. Metabolic drug-drug increasingly been reported (Deng, 2002; Shi and Klotz, 2012). interactions occur when a drug inhibits or induces the activity It is likely that constituents in herbal preparations may module of a drug-metabolising enzyme, which catalyses the or interfere with the pharmacokinetics and pharmacodynamics metabolism of a concomitantly administered drug. Interaction of co-administered drugs, resulting in drug-herb interactions. however is not limited to drugs but includes also other supplements that patients may be taking at the same time including vitamins, minerals, food supplements and herbal COMMON MECHANISMS OF INTERACTION remedies. Herbal medicines have been used worldwide since ancient times. Archeological evidence and pollen analysis from The clinical importance of any drug interaction depends on a Neanderthal burial site in modern day Iraq indicate that the several factors, including the condition of the patient, the drugs use of medicinal plants may be dated back to 50,000 B.C. administered, the route of administration, the environment, the (Solecki and Shanidar, 1975). An estimated one third of adults therapeutic index, as well as the timing of administration of the in the United States use alternative therapies, including herbs drugs (Kremers, 2002). The possible causes of drug interactions (Kauffmanet et al., 2002; Shi and Klotz, 2012). It has also been can be summarized as follows: reported that 20% of the general population in the United Competition for gastrointestinal absorption Kingdom used complementary or alternative medicine in the Binding to plasma proteins course of a year (Zhou et al., 2004). There is a common belief Binding to transport proteins among the general public that herbal preparations are “good for Pharmacodynamic interactions at receptor level humans” as they are “all natural” (Solecki and Shanidar, 1975). Inhibition of metabolism However, they are complex mixtures of bioactive entities that Induction of metabolism may or may not provide therapeutic activity. Usually, the Competition for active renal excretion The gastrointestinal absorption of drugs may be affected by *Correspondence: Chin Eng Ong concurrent use of other agents due to the large surface area of E-mail: [email protected] the tract upon which the drug can be absorbed, bind or chelate, Received February 11, 2014; Accepted August 18, 2014; Published or alter in term of gastrointestinal motility. The mechanisms by August 31, 2014 which drug interactions alter drug distribution include doi: http://dx.doi.org/10.5667/tang.2014.0008 competition for plasma protein binding and displacement from ©2014 by Association of Humanitas Medicine tissue binding sites. And this binding can increase the free This is an open access article under the CC BY-NC license. concentration (and thus the effect) of the displaced drug in (http://creativecommons.org/licenses/by-nc/3.0/) TANG / www.e-tang.org 2014 / Volume 4 / Issue 3 / e17 1 Drug interactions with herbal remedies plasma. Pharmacologic interactions between agonists and therefore harmless, they are not free from adverse effects. A antagonists happen at specific receptor sites, resulting in the recent observational study indicates that herbal supplements are effects of drugs being blocked or changed. From the drug associated with adverse events that include all levels of severity, metabolism perspective, one notable system involved in organ systems, and age groups (Palmer et al., 2003). A relevant metabolic drug interactions is the enzyme system comprising safety concern associated with the use of herbal remedies is the the cytochrome P450 (CYP) monooxygenases. This system risk of interaction with prescription medications. This issue is may be affected by either enzyme induction or enzyme especially important with respect to drugs with narrow inhibition. For instance, drug A induces the body to produce therapeutic indices, such as warfarin or digoxin (Shi and Klotz, more of an enzyme which metabolises drug B. This reduces the 2012). In clinical practice, polypharmacy is common, in effective concentration of drug B, which may lead to loss of its addition to medicines prescribed by their physicians; patients effectiveness. On the other hand, drug C inhibits the production may be taking various over-the-counter medications, vitamins, of the enzyme metabolising drug B, thus an elevation of drug B herbs and food supplements concurrently. All ingested occurs possibly leading to an overdose. The renal excretion of substances have the potential to interact, resulting in various active drug can also be affected by concurrent drug therapy, clinical problems such as therapeutic failure, drug adverse thus altering serum drug level and pharmacologic response. effect and toxicity, and altered patient response to therapy. Herbal remedies are mixtures of more than one active ingredient. Hence, the likelihood of drug-herb interaction is theoretically higher than drug–drug interaction because COMMONLY USED HERBS IMPLICATED IN synthetic drugs usually contain single chemical entities. The DRUG INTERACTION interaction is likely to follow the same pharmacokinetic and pharmacodynamic mechanisms as seen in drug–drug Potential drug-herb interactions have been reported in a wide interactions (Izzo et al., 2002; Shi and Klotz, 2012). Drug–herb variety of laboratory, animal and human studies. Furthermore, interactions can occur when herbs and drugs are co- herbal remedies have been shown to interact clinically with administered and the herbal preparation (one or more many prescribed drugs. Table 1 lists some of the most components) modulates the metabolism of the drugs. Moreover commonly used herbs which have been reported to cause drug herbal components can also be metabolised by CYPs or other interactions. Discussion on how these herbal remedies may drug-metabolising enzymes thus further complicating the affect the pharmacokinetic and pharmacodynamic profiles of mechanism. prescribed drugs will be discussed in the ensuing sections. Danshen CLINICAL RELEVANCE OF DRUG-HERB Danshen, the dried root and rhizome of Salvia miltiorrhiza INTERACTIONS Bunge, is a widely used medicinal plant in China and a complementary medicine in the West. Because of its properties The metabolism of a drug can be altered by another drug or in improving microcirculation, causing coronary vasodilatation, foreign chemical and such interaction can often be clinically inhibiting platelet adhesion and aggregation, suppressing the significant. Inhibition of the metabolism of a drug will lead to formation of thromboxane, and protecting against myocardial an elevation of its concentration in tissues, which might result ischemia, it is widely used either alone or in combination with in various adverse reactions, particularly for drugs with low other herbs for cardiovascular and cerebrovascular diseases therapeutic indices. For example, fluconazole, a potent including angina pectoris, thrombosis, hyperlipidaemia, acute inhibitor of an important human CYP isoform, CYP2C9, ischaemic stroke and hypertension (Cheng, 2007; Gao et al., resulted in reduction of approximately 70% of the metabolic 2012; Lam et al., 2006). Danshen is indexed in the 2010 clearance of S-warfarin, leading to organ bleeding in patients Chinese Pharmacopoeia, with more than 35 formulations and (Black et al., 1996). Inhibition of CYPs has also led to the concoctions containing Danshen water-extracts, ethanolic withdrawal of several marketed drugs during

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